Ligation of the common bile duct in rat liver results in the proliferation of the preexisting bile duct cells which retain normal phenotype with no activation of the hepatic stem cell compartment. The present studies were undertaken 1) to determine whether the immature bile epithelium responds differently to the growth stimulus induced by bile stasis to that seen in the mature adult animals, and 2) whether selective destruction of bile ducts results in the activation of stem cell compartment. In addition the possible involvement of SCF/c-kit, HGF and TGF-alpha in bile duct proliferation was examined. Bile duct ligation was utilized to induce proliferation of the bile epithelial cells. The expression of the full-length alpha-fetoprotein (AFP) was used as an indicator for the activation of the stem cell compartment. AFP was highly and specifically expressed in small bile ducts 7 days after bile duct ligation in the immature rats at ages up to 5 weeks. Although no significant increase in the expression of SCF/c-kit, HGF and TGF-alpha was observed 7 days after ligation of the common bile duct in the adult rats, the expression of these growth factors was significantly increased in the bile duct ligated rats up to 5 weeks of age. These results suggest that the bile duct epithelium in the young rats responds to the bile stasis in a fashion phenotypically similar to that seen during early activation of the hepatic stem cells in the adult liver. A similar activation of liver stem cells as was seen after the bile duct ligation of the young rats was observed when bile duct cells were destroyed in the adult animals by administration of N-OH-acetyl-2-aminofluorene (N-OH-AAF). N-OH-AAF is a carcinogenic metabolite of N-acetyl-2-aminofluorene and it is further activated to an ultimate carcinogen by a membrane-bound deacylase, cytosolic acyltransferase and by sulfotransferase. Sulfotransferase is present mainly in zone I of the liver acini. One to six hours after administration of N-OH-AAF an extensive bile duct destruction was observed, which was followed by the appearance of focal necrosis in zone I hepatocytes. After 72 hr liver morphology was similar to that observed after the ligation of the common bile duct. However after the destruction of the bile ducts by N-OH-AAF the stem cell compartment was involved in the reparation of the ductular system.